Exposure-response modelling of osimertinib in patients with non-small cell lung cancer

Br J Clin Pharmacol. 2024 Dec;90(12):3263-3276. doi: 10.1111/bcp.16199. Epub 2024 Aug 19.

Abstract

Aims: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events.

Methods: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis.

Results: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control.

Conclusions: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.

Keywords: anticancer drugs; lung cancer; modelling and simulation; pharmacokinetic‐pharmacodynamic; population analysis.

MeSH terms

  • Acrylamides* / administration & dosage
  • Acrylamides* / adverse effects
  • Acrylamides* / pharmacokinetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Aniline Compounds* / administration & dosage
  • Aniline Compounds* / adverse effects
  • Aniline Compounds* / pharmacokinetics
  • Aniline Compounds* / therapeutic use
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Dose-Response Relationship, Drug
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • Female
  • Humans
  • Indoles
  • Lung Diseases, Interstitial / chemically induced
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Male
  • Middle Aged
  • Models, Biological
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Piperazines / pharmacokinetics
  • Protein Kinase Inhibitors* / administration & dosage
  • Protein Kinase Inhibitors* / adverse effects
  • Protein Kinase Inhibitors* / pharmacokinetics
  • Pyrimidines
  • Treatment Outcome

Substances

  • osimertinib
  • Acrylamides
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • ErbB Receptors
  • Antineoplastic Agents
  • EGFR protein, human
  • Piperazines
  • Indoles
  • Pyrimidines

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